1-methylthioacyl-benz[a] cyclopenta[f] quinolizines and process for their production



United States Patent 1-METHYLTHi0ACYL-BENZ[a]CYCLOPENTAH] QUINOLIZINESAND PROCESS FOR THEIR PRODUCTION Richard E. Brown, Hanover, and RobertI. Meltzer, Rockaway, N.J., assignors to Warner-Lambert PharmaceuticalCompany, Morris Plains, N.J., a corporation of Delaware N0 Drawing.Filed July 21, 1965, Ser. No. 473,840 4 Claims. (Cl. 260-286) Thisinvention relates to novel substituted quinolizines and moreparticularly it relates to novel substituted quinolizines of theformulas:

wherein R and R may be hydrogen, hydroxy or lower alkoxy of 1 to 6carbon atoms such as methoxy, ethoxy and the like or methylene dioxy; Rmay be hydrogen or lower alkyl of 1 to 6 carbon atoms such as methyl,ethyl, propyl, isopropyl and the like; R may be hydrogen, hydroxy or alower acyloxy group of 1 to 6 carbon atoms such as acetoxy, formyloxyand the like; R may be hydrogen, hydroxy or a lower acyloxy radical of 1to 6 carbon atoms such as acetoxy, formyloxy and the like; and R is anacyl radical such as acetyl, formyl, propionyl, benzoyl, toluyl and thelike and n is an integer of from 1 to 2.

The numbering of the compounds of this invention when n is 2 is asfollows:

CHgS-CH-O Ra and when n is l the numbering is as follows:

3,267,105 Patented August 16, 1966 The compounds of this invention havesteroidal-like activities and are useful in endocrine therapy. They alsoexhibit significant pharmacological activity on the cardiovascularsystem. In use, they may be combined with a nontoxic pharmaceuticalcarrier to form dosage forms such as tablets, capsules, solutions,suspensions, elixirs, suppositories and the like with the activeingredients being present from 1 to 500 mg. per dosage unit. They mayalso be combined with other therapeutic agents such as analgesics, forexample, aspirin or namol xenyrate; antibiotics, for example, thetetracyclines or colimycin; cardiovascular agents, for example, PETN;anti-inflammatory agents, for example, ,B-methasone or ,8-rnethas0ne-17-valerate, or other steroids, for example, quingesterone to enhance andbroaden their therapeutic spectrum. In addition, the compounds of thisinvention are useful as intermediates for the production of other novelsubstituted quinolizines of the formula:

CIlHzORo which are prepared from the compounds of this invention bydesulfurization reactions.

According to the process of this invention, the above compounds (I) areprepared by reacting a compound of the Formula IV:

by treatment with a carboxylic acid such as acetic acid, removing theacetic acid by distillation and adding an acid such as perchloric acidto the reaction mixture and recovering the salt as a precipitate. Thestarting materials of Formulas IV and V, used in the above reaction, areprepared according to the directions described in our copendingapplication, Serial No. 433,166 filed February 3 16, 1965, now US.Patent 3,222,368. The starting materials for compounds IV and V are ketolactams of Formula C below. These are prepared from R and R substitutedphenylalkyla mines of the general Formula A below and substitutedketoacids of the general Formula B below in accordance with the processdescribed in our copending application Serial No. 318,190, filed October23, 1963. The R and R substituted phenylalkylamines such as3,4-diethoxyphenylethylamines are well known compounds which aredescribed in the literature, for example in Chemical Abstracts, vol. 56,page 10006 and by Ide et al. in J.A.C.S., vol. 59, page 726 (1937). Theketoacids of Formula B are prepared according to the process describedin our copending application Serial No. 310,146, filed September 19,1963, using 2-R -cycloalkane-L3- diones as starting material. Such 2-R-cycloalkane-L3- diones are well known in the art and may be preparedaccording to the procedure of Panouse and Sannie published in Bull. Soc.Chim. France, 1955, page 1036. See also The keto lactam (C) is thencyclized with phosphorous oxychloride and converted to IV or V inaccordance with the process set forth in our .copending applicationSerial No. 248,872, filed January 2, 1963.

The compounds of this invention are obtained by the above-describedprocess as a mixture of epimers about the carbon atom bearing the sulfursubstituent and these epimers are also included within the scope of thisinvention.

The following examples are included in order further to illustrate theinvention.

EXAMPLE 1 1,2,3,3a,5,6,10b,11,12,12a decahydro 8 methoxy-IZamethyl1-[acetoxy(methylthi0)acetyl]benzo[a]cyclopenta[f]quinolizine A solutionof 2.0 g. of 1,2,3,3a,5,6,10b,11,12,12adecahydro 8methoxy-12a-methyl-l-(methylsulfinyl) acetyl-benzo[a]cyclopenta[f]quinolizine in 25 ml. of acetic acid is heated for 2 hours on asteam bath. The solution is concentrated to dryness and the residue isdiluted with 20 m1. of Water. The mixture is extracted well withmethylene chloride. The methylene chloride solution is washed with 5%sodium bicarbonate solution, dried and the solvent is removed bydistillation. The oily residue crystallizes slowly on standing to give1,2,3,3a,5,6, 10b,1l1,12,12adecahydro-8-methoxy-12a-methyl-1-[acetoxy(methylthio) acetyl]benzo [a]cyclopenta [f] quinolizine, as a solid mixture of epimers about thesulfur-bearing carbon atom, M.P. 94102 C. after recrystallization \fIOmethanol.

EXAMPLE 2 2,3,3a,5,6,11 ,12,12a octahydro-8-meth0xy-12a-methyl-1[acetoxy(methylthi0)acetyl] 1H-benz[a]cycl0pent[f] quinoliziniumperchlorate use (13:0

Alt

In the same way as described in Example 1, 1.0 g. of 1,2,3,3a,5,6,12,12aootahydro-8-methoxy-12a-methyl-1- (methylsulfinyl)acetylbenzo[a]cyclopcnta[f]quinolizine is treated with acetic acid. The aceticacid is removed by distillation, the residue is taken up in water and anexcess of 10% perchloric acid is added to the aqueous solution to give2,3,3=a,5,6,11,12,12a-octahydro-8-methoxy- 12amethyl-1-[acetoxy(methylthio)acetyl]-1H-benz[a] cyclopentif]q'uinollizinium perchlorate as a pale yellow amorphous solid,M.P. 102 C. The product shows strong sharp carbonyl bands in theinfrared at 1710 and 1740 cmf EXAMPLE 3 1,2,3,3a,5,6,10b,11,12,12adecahydro 8 methoxy-lZamethyl1-[acetoxy(methylthio)acetyl]LII-dihydroxybenz0[a]cycl0penta[f]quin0lizineCHaO In the same way as described in Example 1, 1.0 g. of1,2,3,3a,5,6,10b, 11,12,12-a decahydro 8 methoxy-12amethyl l-( methylsulfinyl)acetyl-1,1l-dihydroxybenzo-[a] cyclopenta[f]quinolizinegives 1,2,3,3a,5,6,10b,11,12,12 adecahydro8-methoxy-12a-methyl-1-[acet-oxy(methylthio) acetyl]l,11dihydroxybenzo[a]cyclopenta[f]quinolizine as an oily mixture of epimersabout the carbon atom bearing the sulfur atom. One of the epimers can beobtained in crystalline form by trituratin-g the oil with ethanol. Thismaterial melts at 157 159 C. after recrystallization from ethanol.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

wherein R and R each are members selected from the group consisting ofhydrogen, hydroxy, lower alkoxy and methylene dioxy; R is a member ofthe 'group consisting of hydrogen and lower alkyl; R is a member of thegroup consisting of hydrogen, hydroxy and lower acyloxy of a carboxylicacid; R is a member selected from the group consisting of hydrogen,hydroxy and lower acyloxy of a carboxylic acid; R is acyl of acarboxylic acid and n is integer of from 1 to 2.

2. 1,2,3,3a,5,6,10b,11,12,l2a-decahydro-8-methoxy-12amethyl-1-[acetoxy(methylthio) acetylJbenzo [a] cyclopenta [if] quino'lizine.

3. 2,3,3a,5,6,ll,12,12a octahydno 8 methoxy 12amethyl1-[acetoxy(methy1thio) acetyl] -1H-benz[a]fcycl0- pent [f] quinoliziniumperchlorate.

4. 1,2,3,3a,5,6,10b,11,12,12a-decahydro 8 methoxy- 12a methyl 1[acetoxy(methylthio)acetyl]1,11dihydroxybenzo[a]cyc1openta[f]quino1izine.

No references cited.

ALEX MAZEL, Primary Examiner.

DONALD G. DAUS, Assistant Examiner.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAS: